Aralkyl aliphatic sulfoxide oral,parenteral and rectal dosage units for pain,fever and inflammation



United States Patent ARALKYL ALIPHATIC SULFOXIDE ORAL, PAREN- TERAL AND RECTAL DOSAGE UNITS FOR PAIN, FEVER AND INFLAMMATION Clifford H. Shunk and Tsung-Ying Shen, Westfield, N.J.,

assignors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Continuation-impart of application Ser. No. 458,392, May 24, 1965. This application Aug. 1, 1966, Ser. No. 569,054

Int. Cl. A61k 27/00 US. Cl. 424-337 15 Claims ABSTRACT OF THE DISCLOSURE Method of treating inflammation and anti-inflammatory compositions containing an aralkyl aliphatic sulfoxide.

This application is a continuation-in-part of our application Ser. No. 458,392, filed May 24, 1965, now abandoned.

This invention relates to a method of treating inflammation in its varying manifestations, utilizing novel antiinflammatory compositions containing an aralkyl alkyl sulfoxide. In addition, these novel compositions exhibit potent analgesic and antipyretic activity and, therefore, this invention also relates to analgesic and antipyretic methods and compositions. More particularly, this invention is concerned with the use of benzyl methyl sulfoxide as the active therapeutic ingredient in the herein described methods and compositions.

Benzyl methyl sulfoxide and the related aralkyl sulfoxides of this invention represent a new milestone in the continuing search for potent, low toxicity, anti-inflammatory agents. These sulfoxides provide a unique structureactivity relationship which not only has resulted in high anti-inflammatory, antipyretic, and analgesic potency, but also appear to exhibit a biological profile quite different from the salicylates and phenylbutazone.

It is an object of this invention to provide a method of treatment of inflammation and associated pain and fever. It is also an object of this invention to provide analgesic and antipyretic methods for the relief and treatment of pain and fever not symptomatically related to an inflammatory indication. Another object is to provide an entirely new class of anti-inflammatory, analgesic and antipyretic compositions.

The above and other objects of this invention are accomplished by treatment of a disease condition, symptomatically evidenced by pain, fever and inflammation, either as essential or concomitant phenomena of the disease, which comprises the administration in dosage unit form of a pharmaceutically acceptable composition containing a therapeutically effective amount of an aralkyl sulfoxide, such as benzyl methyl sulfoxide. The sulfoxides of this invention can be represented by the following formula:

X R O wherein R represents alkyl of from 1 to about 16 carbon atoms, preferably, of from 1 to about 4 carbons, such as methyl, ethyl, propyl and butyl, cycloloweralkyl such as cyclopentyl and cyclohexyl, loweralkenyl, haloloweralkenyl, haloloweralkyl, or nitroloweralkyl. R represents hydrogen, halo, loweralkyl, nitroloweralkyl, or loweralkylsulfoxyl. X and Y are hydrogen, halo, nitro, or loweralkyl. Loweralkyl and loweralkenyl means groups of from 1 to about 3 carbons, and halo refers to chloro and bromo.

A preferred embodiment of this invention is a method of treating a disease which is symptomatically character- 3,466,377 Patented Sept. 9, 1969 ized by pain, fever and/ or inflammation which comprises the administration in dosage unit form of between about 0.01 and 5 gm. of a benzyl methyl sulfoxide per day. On a kilogram basis, it is preferred to utilize between about 0.5 mg./kg. and 70 mg./kg. per day to a patient of the aralkyl hydrocarbyl sulfoxides of this invention.

Another embodiment of this invention is the provision of pharmaceutical compositions in dosage unit form which comprise from about 5 to 500 mg, and preferably from 25 to 250 mg, of an aralkyl hydrocarbyl sulfoxide of the above formula. Benzyl methyl sulfoxide, in oral dosage unit form, comprising about 25 to about 500 mg. is a preferred pharmaceutical composition of this invention.

The aralkyl hydrocarbyl sulfoxide active ingredient of the compositions of this invention demonstrates significant anti-inflammatory analgesic and antipyretic properties. For example, anti-inflammatory activity of a high order of potency was shown for benzyl methyl sulfoxide against carrageenan edema, using the method set forth in Proc. Soc. Exp. Biol. Med. 3: 544 (1962). The minimum dose required for dependable demonstration of anti-inflammatory activity was about 3 mg./kg. This compound is also a potent analgesic, as has been shown by antinociceptive testing by the infiammed foot technique of Randall & Selitto, Arch. Int. Parmacodyn. 11: 409 (1957), as modified by Gilfoil et al. (1963) and Winter et al. (1965). Benzyl methyl sulfoxide raised the pain threshold most significantly when compared to the controls treated with the corresponding vehicle exclusive of said sulfoxide. Significant activity was observed at dosages as low as 10 mg./kg. and high potency was observed at 30 mg./kg. and mg./ kg. It is significant to note that the pain threshold was raised in both the infected and noninfected foot. This is in contrast to currently used analgesics which raise the pain threshold in the infected foot only.

An analgesic effect was also demonstrated in treatment of arthritis induced hyperesthesia, utilizing an extremely sensitive technique which quantitatively records vocalization reduction. According to this test, benzyl methyl sulfoxide is a potent analgesic. In addition, the sulfoxides of this invention, as exemplified by benzyl methyl sulfoxide, exhibit potent antipyretic activity in yeast induced fever tests. Benzyl methyl sulfoxide was demonstrated to have antipyretic activity at dosages as low as 6.25 mg./kg. Similarly, anti-inflammatory, analgesic and antipyretic activity can be demonstrated for other active sulfoxide ingredients of this invention, e.g. benzyl ethyl sulfoxide, benzyl propyl sulfoxide, benzyl butyl sulfoxide, benzyl t-butyl sulfoxide, benzyl decyl sulfoxide, benzyl dodecyl sulfoxide, benzyl nonyl sulfoxide, benzyl hexyl sulfoxide, benzyl isobutyl sulfoxide, benzyl isopropyl sulfoxide, benzyl octyl sulfoxide, benzyl 1,2dichlorovinyl sulfoxide, p-chlorobenzyl 1,2-dichlo-rovinyl sulfoxide and the like.

Thus, it can be seen that the novel sulfoxide compositions of this invention exercise anti-inflammatory, analgesic and antipyretic activity. In general they are indicated for a wide variety of conditions where one or more of the symptoms of inflammation, fever and pain are manifested.

The pharmaceutical compositions may be in a form suitable for oral use, for example, as tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, colouring agents and preserving agents in order to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active sulfoxide ingredient in admixture with nontoxic p-harmaceutically acceptable excipients which are suitable for manufacture of tablets. These excipients may be, for example, inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example maize starch, or alginic acid; binding agents, for example starch, gelatine or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastro-intestinal tract and thereby provided a sustained action over a longer period.

Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with an oil medium, for example arachis oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active aralkyl hydrocarbyl sulfoxides in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The said aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more fiavouring agents and one or more sweetening agents, such as sucrose, saccharin, or sodium or calcium cyclamate.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid parafiin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and fiavouring agents may be added to pro vide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, fiavouring and colouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures or these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean lecithin, and esters of partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and fiavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and fiavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenternally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.

The sulfoxide compositions of this invention may also be in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable nonirritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

The pharmaceutical compositions may be tableted or otherwise formulated so that for every 100 parts by weight of the composition there are present between 5 and parts by weight of the active ingredient and preferably between 25 and 85 parts by weight of the active ingredient. The dosage unit form will generally contain between about mg. and about 500 mg. of the active ingredient of the formula stated above.

From the foregoing pharmaceutical tests it is apparent that the compositions of this invention can be administered orally, parenterally, and rectally. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection or infusion techniques.

The dosage regimen in carrying out the methods of this invention is that which insures maximum therapeutic response until improvement is obtained and thereafter is the minimum effective level which gives relief. Thus, in general, the dosages are those that are therapeutically effective in the treatment of inflammation, pain and fever. In general, the daily dose can be between about 0.5 mg./ kg. and 70 mg./kg., bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patients weight, general health, age and other factors which may influence response to the drug.

It is expected that the sulfoxide compositions of this invention will generally be administered in dosage units of between 5 and 500 mg. of active ingredient. Preferred compositions for ease of administration are in oral dosage unit form, e.g., tablets or capsules, containing between 25 and 500 mg. of a sulfoxide of this invention.

This invention is further demonstrated by the following examples in which all parts are by weight.

EXAMPLE 1 A mixture of 250 parts of benzyl methyl sulfoxide and 25 parts of lactose is granulated with suitable water, and to this is added 100 parts of maize starch. The mass is passed through a 16 mesh screen. The granules are dried at a temperature below 60 C. The dry granules are passed through a 16 mesh screen, and mixed with 3.8 parts of magnesiumstearate. They are then compressed into tablets suitable for oral administration.

The benzyl methyl sulfoxide used in the foregoing example may be replaced by 25, 100 or 500 parts of benzyl methyl sulfoxide, benzyl propyl sulfoxide, benzyl isopropyl sulfoxide, benzyl n-butyl sulfoxide, benzyl isobutyl sulfoxide, benzyl t-butyl sulfoxide, benzyl ethyl sulfoxide, benzyl dodecyl sulfoxide, 2-chlorobenzyl methyl sulfoxide, u-methane sulfoxyl benzyl methyl sulfoxide, and the like sulfoxides of this invention to produce tablets suitable for oral administration as an anti-inflammatory,

antipyretic and/or analgesic according to the method of this invention.

- EXAMPLE 2 A mixture of 50 parts of benzyl ethyl sulfoxide, 3 parts of the calcium salt of lignin sulphonic acid, and 237 parts of water is ball-milled until the size of substantially all of the particles of benzyl ethyl sulfoxide is less than microns. The suspension is diluted with a solution containing 3 parts of sodium carboxymethyl cellulose and 0.9 part of the butyl ester of p-hydroxy benzoic acid in 300 parts of water. There is thus obtained an aqueous suspension suitable for oral administration for therapeutic purposes.

EXAMPLE 3 A mixture of 250 parts of benzyl butyl sulfoxide, 200 parts of maize starch and 30 parts of alginic acid is mixed with a suflicient quantity of a 10% aqueous paste of maize starch, and granulated. The granules are dried in a current of warm air and the dry granules are then passed through a 16-mesh screen, mixed with 6 parts of magnesium stearate and compressed into tablet form to obtain tablets suitable for oral administration.

EXAMPLE 4 A mixture of 500 parts benzyl decyl sulfoxide, 60 parts of maize starch and 20 parts of gum acacia is granulated with a sufficient quantity of water. The mass is passed through a 12-mesh screen and the granules are dried in a current of warm air. The dry granules are passed through a l6-mesh screen, mixed with 5 parts of magnesium stearate and compressed into tablet form suitable for oral administration.

The aralkyl hydrocarbyl sulfoxides of this invention are produced by well-known techniques, such as oxidation of the corresponding sulfide with dilute sodium periodate or hydrogen peroxide. These methods are more fully set forth in Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York, pages 801-803 (1953), and by the following examples.

EXAMPLE 5 2-chlorobenzyl methyl sulfide (6.2 g.) is dissolved in 80 ml. of glacial acetic acid and 4.1 ml. of 30% hydrogen peroxide solution is added slowly with stirring and cooling at 22-23 C. After the exothermic phase of the reaction has subsided, the cooling bath is removed and the solution is stirred at room temperature for 1 hour. The solution is diluted with 80 ml. of water and treated with sodium bisulfite to consume excess hydrogen peroxide. After diluting with 3 volumes of water, the solution is extracted 5 times with 1-00 ml. of chloroform. The extract is dried over magnesium sulfate, and concentrated under reduced pressure to an oil weighting 8.5 g. Distillation provides 6.0 g. of product with -B.P. 108-111 C./ 0.005 mm.

Analysis.-Calculated for C H ClOS: C, 50.92; H, 4.81%. Found: C, 51.00; H, 4.55%.

Employing the method of Example 5 but substituting for 2-chlorobenzyl methyl sulfide an equimolar amount of the appropriate sulfide, there is obtained 2-methylbenzyl methyl sulfoxide, 3-nitrobenzyl cyclopentyl sulfoxide, 4- bromobenzyl methyl sulfoxide, 2,4-dimethylbenzyl-2- chloroethyl sulfoxide, and 3,-4-dichlorobenzyl-1,2-dichlorovinyl sulfoxide.

EXAMPLE 6 Benzyl bis-methyl sulfoxide A solution of 16.6 g. of sodium metaperiodate in 250 ml. of water is added, with stirring and cooling to 0-5 C., to a solution of 7.0 g. of benzyl bis-methyl sulfide in 250 ml. of methanol and stirring is continued at 0-5 for 14 hours. The mixture was filtered, and the filtrate is extracted with 3 x 200 m1. of methylene chloride. The extract is dried over magnesium sulfate and concentrated under reduced pressure at 25 to give 7.9 g. of oil which crystallizes on standing. The solids are recrystallized from methanol-ether solution to give 2.43 g. of product, M.P. -170". This is recrystallized from methylene chloride petroleum ether to give 1.56 g., M.P. -172 (a). From the filtrate is obtained 394 mg. of product, M.P. l36-l38 C. ()3). The compound designated a. on further recrystallization gives 864 mg., M.P. 172-173 C.

Analysis.Calculated for C H O S C, 50.00; H, 5.60; S, 29.60%. Found: (a) C, 50.29; H, 5.54; S, 30.24%; (B) 49.69; H, 5.04; 30.26%.

EXAMPLE 7 Benzyl 1,1-dimethyl-2-nitroethyl sulfoxide Utilizing the method of Example 5 but employing 8.1 g. of benzyl 1,1-dimethyl-2-nitroethyl sulfoxide in place of the 2-chlorobenzyl methyl sulfide, there is obtained benzyl 1,1-dimethyl-2-nitroethyl sulfoxide.

EXAMPLE 8 a-Chlorobenzyl methyl sulfoxi'de Utilizing the method of Example 5 but employing 6.2 g. of a-chlorobenzyl methyl sulfide in place of the 2- chlorobenzyl methyl sulfide, there is obtained a-chlorobenzyl methyl sulfoxide.

Similarly prepared, according to Example 8, using the appropriate sulfide are u-methylbenzyl ethyl sulfoxide, and a-nitromethylbenzyl methyl sulfoxide.

What is claimed is:

1. A method of treating a disease exhibiting at least one of the symptoms of pain, fever, and inflammation, which comprises the oral, parenteral or rectal administration in unit dosage form of a pharmaceutically acceptable composition containing a therapeutically effective amount of a compound having the following formula:

wherein R is a member selected from the group consisting of alkyl of from 1 to 16 carbon atoms, cyclolower alkyl, loweralkenyl, haloloweralkyl, nitroloweralkyl, and lowersulfoxyl; and X and Y are members selected from. the group consisting of hydrogen, halo, nitro, and loweralkyl, wherein loweralkyl and loweralkenyl mean from 1 to 3 carbons, and halo refers to chloro and bromo.

2. A method of treating a disease, exhibiting at least one of the symptoms of pain, fever and inflammation, which comprises the oral, parenteral or rectal administration in dosage unit form of a therapeutically effective amount of benzyl methyl sulfoxide.

3. The method of claim 1 wherein said effective amount is between about 0.5 mg./ kg. and 70 mg./kg. per day.

4. The method of claim 2 wherein said effective amount is between about 0.5 mg./kg. and 70 mg./kg. per day.

5. The method of claim 1 wherein said composition is in a parenteral dosage unit form suitable for oral administration.

6. The method of claim 2 wherein said composition is in a parenteral dosage unit form suitable for oral administration.

7. The method of claim 1 wherein said composition is in a dosage unit form suitable for parenteral administration.

8. The method of claim 2 wherein said composition is in a dosage unit form suitable for parenteral administration.

9. A pharmaceutical composition in oral dosage unit form comprising an oral pharmaceutical carrier vehicle and between about 25 and 250 mg. of benzyl methyl sulfoxide.

10. A method of treating a disease exhibiting at least one of the symptoms of pain, fever, and inflammation, which comprises the oral, parenteral or rectal administration in unit dosage form of a pharmaceutically acceptable composition containing a therapeutically effective amount of a compound having the following formula:

X R o wherein R is a member selected from the group consisting of alkyl of from 1 to 4 carbon atoms, cyclopentyl, cyclohexyl, lower alkenyl, haloloweralkenyl, haloloweralkyl, and nitrolo-weralkyl; R is a member selected from the group consisting of hydrogen, haloloweralkyl, nitroloweralkyl, and loweralkylsulfoxyl; and X and Y are members selected from the group consisting of hydrogen, halo, nitro, and loweralkyl, wherein loweralkyl and lower alkenyl mean from 1 to 3 carbons, and halo refers to chloro and bromo.

11. A pharmaceutical composition in oral, parenteral or rectal dosage unit form comprising an oral, parenteral or rectal pharmaceutical carrier vehicle and between about 5 and 500 mg. of a compound having the following formula:

X R o T H--SR wherein R is a member selected from the group consisting of alkyl of from 1 to 4 carbons, cyclopentyl, cyclohexyl, lower alkenyl, haloloweralkenyl, haloloweralkyl, nitroloweralkyl, and loweralkylsulfoxyl; and X and Y are members selected from the group consisting of hydrogen, halo, nitro, and loweralkyl, wherein loweralkyl and loweralkenyl mean from 1 to 3 carbons, and halo refers to chloro and bromo.

wherein R is a member selected from the group con sisting of alkyl of from 1 to 16 carbon atoms, cycloloweralkyl, loweralkenyl, haloloweralkenyl, haloloweralkyl, and nitroloweralkyl; R isa member selected from the group consisting of hydrogen, haloloweralkyl, nitroloweralkyl, and loweralkylsulfoxyl; and X and Y are members selected from the group consisting of hydrogen, halo, nitro, and loweralkyl, wherein loweralkyl and loweralkenyl mean from 1 to 3 carbons, and halo refers to chloro and bromo.

13. The composition of claim 12 wherein said compound is benzyl methyl sulfoxide.

14. The composition of claim 12 in oral dosage unit form.

15. The composition of claim 12 in parenteral dosage unit form.

References Cited UNITED STATES PATENTS 3,196,184 7/1965 Berry 260 -607 3,288,860 11/1966 Lyness et al. 260607 S. K. ROSE, Primary Examiner U.S. Cl. X.R. 260-607 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N 3,466,377 Dated September 9, 1969 Inventor(s) Clifford H. Shunk and Tsunq-Yinq Shen It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

r- Column 6 claim 1 line 44, after "lowersulfoxyl;

and column 7, claim 11, line 31, after "loweralkylxulfoxyl;" add R' is a member selected from the group consisting of hydrogen, haloloweralkyl, nitroloweralkyl and lower alkylsulfoxyl;

SIGNED AND SEALED JUN 2 3 1970 Attest:

"ml-Ml E. SO Um, JR-

Edmrd M.Flc 'J'- flomissione'r of Patents Anesfing Officer 

